# Characterizing noncoding GWAS variants in acute lymphoblastic leukemia treatment outcome

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2020 · $444,543

## Abstract

PROJECT SUMMARY
Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer, and although overall survival rates
of ALL have substantially improved, resistance to antileukemic agents remains a major clinical problem.
Antileukemic drug resistance is predictive of poor disease outcome and is commonly observed in ALL patients
that have relapsed, who have a low overall survival rate of only 40%. The mechanisms that cause ALL relapse
and drug resistance remain poorly understood. To address how inherited genomic variability contributes to these
mechanisms, genome wide association studies (GWASs) have identified DNA sequence variation associated
with ALL treatment outcome. However, since these variants are noncoding in nature, their connection to gene
function, ALL biology and antileukemic drug resistance has been difficult to establish. Moreover, given that
hundreds of variants are typically in strong linkage disequilibrium with the associated variant, pinpointing causal
variants at GWAS loci has been challenging. To address these challenges, we have generated functional
genomic maps of the ALL genome, including the precise locations of noncoding regulatory elements in >40 ALL
samples. Through rigorous open chromatin-fine mapping using our ALL genome maps, and by integrating our
results with drug resistance phenotypes from primary ALL cells obtained from patients at St. Jude (SJ), we
identified 3229 variants at 125 GWAS loci associated with ALL treatment outcome that are predicted to have an
impact on gene regulation, leukemic cell biology and antileukemic drug resistance. Using these fine-mapped
variants, we propose an integrative strategy for identifying candidate causal variants associated with ALL
treatment outcome, and a rational experimental system for functionally linking these variants and their target
genes to antileukemic drug resistance. In Aim 1, we will perform massively parallel reporter assays (MPRAs) on
>3200 fine-mapped variants to assess their gene regulatory activities and to identify allele-specific differences
in activity. In Aim 2, we will employ a polygenomic strategy by integrating our MPRA results with diverse genomic
datasets to prioritize and rank fine-mapped variants by their likelihood of being causal. For this effort, we will
capitalize on the unique and rich resources available at SJ, including extensive genomic characterizations and
drug resistance phenotypes from large ALL patient cohorts, as well as ongoing genomic characterizations for all
new and/or relapsed patients. We will functionally validate the role of the top 20 ranked candidate causal variants
on antileukemic drug resistance using CRISPR technology and chemotherapeutic drug viability assays in human
ALL cell lines. We will also identify GWAS target genes and functionally assess their role in antileukemic drug
resistance in human ALL cell lines and in patient-derived xenograft mouse models of pediatric ALL. Collectively,
our proposal will uncove...

## Key facts

- **NIH application ID:** 9983634
- **Project number:** 5R01CA234490-02
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Daniel Savic
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $444,543
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983634

## Citation

> US National Institutes of Health, RePORTER application 9983634, Characterizing noncoding GWAS variants in acute lymphoblastic leukemia treatment outcome (5R01CA234490-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9983634. Licensed CC0.

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